Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures

Sandström, Jenny; Zoia, Debora; Althaus, Jorane; Antinori, Paola; Mermoud, Julien; Pak, Hui Song; Scherl, Alexander; Monnet‐Tschudi, Florianne

doi:10.1016/j.toxlet.2014.02.001

Cited by 17 publications

(15 citation statements)

References 75 publications

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“…Glial fibrillary acidic protein (GFAP) and related glial biomarkers are used in neurotoxicity studies to distinguish glial cells from neurons (Monnet-Tschudi et al 2000;O'Callaghan and Sriram 2005;Monnet-Tschudi et al 2007;Sandström von Tobel et al 2014). A highcontent analysis method for gliosis induced by treatment with neurotoxicants has been developed on the basis of cocultures of rat neurons and astrocytes (Anderl et al 2009).…”

Section: Gliosismentioning

confidence: 99%

In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities

et al. 2016

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Neurotoxicity and developmental neurotoxicity are important issues of chemical hazard assessment. Since the interpretation of animal data and their extrapolation to man is challenging, and the amount of substances with information gaps exceeds present animal testing capacities, there is a big demand for in vitro tests to provide initial information and to prioritize for further evaluation. During the last decade, many in vitro tests emerged. These are based on animal cells, human tumour cell lines, primary cells, immortalized cell lines, embryonic stem cells, or induced pluripotent stem cells. They differ in their read-outs and range from simple viability assays to complex functional endpoints such as neural crest cell migration. Monitoring of toxicological effects on differentiation often requires multiomics approaches, while the acute disturbance of neuronal functions may be analysed by assessing electrophysiological features. Extrapolation from in vitro data to humans requires a deep understanding of the test system biology, of the endpoints used, and of the applicability domains of the tests. Moreover, it is important that these be combined in the right way to assess toxicity. Therefore, knowledge on the advantages and disadvantages of all cellular platforms, endpoints, and analytical methods is essential when establishing in vitro test systems for different aspects of neurotoxicity. The elements of a test, and their evaluation, are discussed here in the context of comprehensive prediction of potential hazardous effects of a compound. We summarize the main cellular characteristics underlying neurotoxicity, present an overview of cellular platforms and read-out combinations assessing distinct parts of acute and developmental neurotoxicology, and highlight especially the use of stem cell-based test systems to close gaps in the available battery of tests.

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Section: Gliosismentioning

confidence: 99%

In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities

et al. 2016

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“…S1). Traditional approaches to study astrocyte-neuron interactions include re-aggregating brain cultures, more defined co-cultures in 2D (Garwood et al 2011;Sandstrom von Tobel et al 2014), or 3D formats (Puschmann et al 2013). An added benefit of defined co-cultures is that human neurons can be studied.…”

Section: Introductionmentioning

confidence: 99%

Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation

et al. 2016

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were involved in this neurodegeneration. The neurotoxicity-mediating effect of IMA was faithfully reproduced by human astrocytes. Moreover, glia-dependent toxicity was also observed, when IMA cultures were stimulated with CM, and the culture medium was transferred to neurons. Such neurotoxicity was prevented when astrocytes were treated by p38 kinase inhibitors or dexamethasone, whereas such compounds had no effect when added to neurons. Conversely, treatment of neurons with five different drugs, including resveratrol and CEP1347, prevented toxicity of astrocyte supernatants. Thus, the sequential IMA-LUHMES neuroinflammation model is suitable for separate profiling of both glial-directed and directly neuroprotective strategies. Moreover, direct evaluation in co-cultures of the same cells allows for testing of therapeutic effectiveness in more complex settings, in which astrocytes affect pharmacological properties of neurons.Keywords LUHMES · Astrocyte · p38 kinase · Neuroinflammation · Neuropharmacology Abstract Astrocytes, the largest cell population in the human brain, are powerful inflammatory effectors. Several studies have examined the interaction of activated astrocytes with neurons, but little is known yet about human neurotoxicity under such situations and about strategies of neuronal rescue. To address this question, immortalized murine astrocytes (IMA) were combined with human LUHMES neurons and stimulated with an inflammatory (TNF, IL-1) cytokine mix (CM). Neurotoxicity was studied both in co-cultures and in monocultures after transfer of conditioned medium from activated IMA. Interventions with >20 drugs were used to profile the model system. Control IMA supported neurons and protected them from neurotoxicants. Inflammatory activation reduced this protection, and prolonged exposure of co-cultures to CM triggered neurotoxicity. Neither the added cytokines nor the release of NO from astrocytes Liudmila Efremova and Petra Chovancova have contributed equally to this study.

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“…But, because of the neuroprotective or neuroreparative potential of neuroinflammation, it is possible that the consequences of neuroinflammation will be in a first step positive, with microglia expressing the M2 phenotype. After an exposure arrest and a temporal delay (Sandström et al, 2014), or in the presence of cell death Hanish and Kettenmann, 2007), microglia can acquire the M1 neurodegenerative phenotype. Therefore, it is rather the qualitative phenotype of neuroinflammation that will induce neurodegeneration.…”

Section: Quantitative Considerationmentioning

confidence: 99%

“…The evolution of regulation towards mechanistically-driven approaches for supporting hazard identification implies also the development of in vitro testing. Three-dimensional cultures, prepared from fetal rat brain cells, exhibiting an histotypic organisation comprising all types of brain cells (specifically microglial cells and astrocytes, as effector cells of neuroinflammation) and allowing long-term maintenance for repeated exposure and for studying the evolution of neuroinflammatory phenotypes, are already available (Alépée et al, 2014;Sandström et al, 2014). Similar 3D cultures prepared from human pluripotent stem cells are in development (Schwartz et al, 2015;Sandström et al, 2017).…”

Section: Considerations For Potential Applications Of the Aop (Optional)mentioning

confidence: 99%

“… Pro-and anti-inflammatory cytokine expression (IL-1β; TNF-α, Il-6, IL-4); or expression of immunostimmulatory proteins (e.g. MHC-II)  Itgam, CD86 expression as markers of M1 microglial phenotype  Arg1, MRC1, as markers of M2 microglial phenotype (for descriptions of techniques, see also Falsig 2004;Kuegler 2010;Monnet-Tschudi et al, 2011;Sandström et al, 2014;von Tobel et al, 2014) Regulatory example using the KE:Measurement of glial fibrillary acidic protein (GFAP) in brain tissue, whose increase is a marker of astrocyte reactivity, is required by the US EPA in rodent toxicity studies for fuel additives (40 CFR 79.67), but is optional for other toxicant evaluations.…”

Section: How It Is Measured or Detectedmentioning

confidence: 99%

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Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors during brain development leading to neurodegeneration with impairment in learning and memory in aging

Tschudi-Monnet

FitzGerald

2018

OECD Series on Adverse Outcome Pathways

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This Adverse Outcome Pathway (AOP) on chronic binding of antagonist to N-methyl-Daspartate receptors (NMDARs) during brain development leading to neurodegeneration with impairment in learning and memory in aging, has been developed under the auspices of the OECD AOP Development Programme, overseen by the Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST), which is an advisory group under the Working Group of the National Coordinators for the Test Guidelines Programme (WNT). The AOP has been reviewed internally by the EAGMST, externally by experts nominated by the WNT, and has been endorsed by the WNT and the Working Party on Hazard Assessment (WPHA) in June 2018. Through endorsement of this AOP, the WNT and the WPHA express confidence in the scientific review process that the AOP has undergone and accept the recommendation of the EAGMST that the AOP be disseminated publicly. Endorsement does not necessarily indicate that the AOP is now considered a tool for direct regulatory application. The Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology agreed to declassification of this AOP in September 2018. This document is being published under the responsibility of the Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology. The outcome of the internal and external reviews are publicly available respectively in the AOP Wiki and the eAOP Portal of the AOP Knowledge Base at the following links: [internal review] [external review].

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Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures

Cited by 17 publications

References 75 publications

In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities

In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities

Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors during brain development leading to neurodegeneration with impairment in learning and memory in aging

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